Formation of a functional nervous system requires the proper development and remodeling of dendrites and dendritic spines, the primary sites of excitatory synapses in the brain. Rho family GTPases play critical roles in regulating these processes. In particular, the Rho GTPase Rac promotes dendritic arborization and the formation and maintenance of spines. Precise spatio-temporal regulation of Rac activity is essential for its function, since aberrant Rac signaling results in dendrite and spine abnormalities and cognitive disorders including mental retardation. Despite its importance, the mechanisms that regulate Rac signaling in neurons remain poorly understood. We previously identified the Rac-specific activator Tiam1 as a critical regulator of dendrite, spine, and synapse development. We demonstrated that Tiam1 mediates both NMDA receptor- and EphB receptor-dependent spine development by coupling these receptors to Rac signaling pathways that control actin cytoskeletal remodeling and protein synthesis. Recently, we have also identified the Rac-specific inhibitor Bcr as a Tiam1-interacting protein that blocks Tiam1-induced Rac activation and actin remodeling. Overexpression and knockout experiments indicate that Bcr restricts the formation and growth of spines and dendrites. The complex between Tiam1 and Bcr may serve as an on-off switch for precisely regulating Rac signaling in neurons, which is essential for the proper formation and remodeling of spines, synapses, and dendrites. To test this hypothesis, we propose the following specific aims: 1) to determine the role of Bcr in restricting synapse development and dendritic growth; 2) to identify the mechanisms by which EphB and NMDA receptors regulate the Tiam1-Bcr complex, and determine the consequences on Rac activation and synapse development; and 3) to elucidate the role of the Tiam1-Bcr complex in regulating N-cadherin-mediated synaptic adhesion. To address these questions, we will use a multifaceted approach employing a combination of molecular, cellular, biochemical, and high-resolution imaging techniques. Results from the proposed studies will provide critical insight into the fundamental mechanisms that regulate Rac activation and Rac-dependent synaptic and dendritic development in neurons, and help to elucidate how disruptions in Rac GTPase signaling give rise to cognitive disorders such as mental retardation. PUBLIC HEALTH RELEVANCE: We propose to investigate the mechanisms that regulate how connections in the brain (synapses) form during development and how they remodeling during processes like learning and memory. We are studying a particular signaling pathway that causes mental retardation when mutated in humans. Results from our studies should provide new insight into the fundamental mechanisms of brain development and memory formation, and should enhance our understanding of how disruptions in these processes give rise to brain disorders such as mental retardation.